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Phenotypic and functional translation of IL33 genetics in asthma

Phenotypic and functional translation of IL33 genetics in asthma
Phenotypic and functional translation of IL33 genetics in asthma

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1, FEV 1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species–capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

IL33 SNPs, asthma phenotypes, bronchial epithelium, eQTL, functional translation
0091-6749
144-157
Ketelaar, Maria E.
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Sin, D.D.
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Vonk, J.M.
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van den Berge, M.
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Koppelman, G.H.
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Sayers, I.
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Nawijn, M.C.
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Ketelaar, Maria E., Portelli, Michael A., Dijk, F. Nicole, Shrine, N., Faiz, Alen, Vermeulen, C.J., Xu, C.J., Hankinson, J., Bhaker, S., Henry, A.P., Billington, C.K., Shaw, D.E., Johnson, S.R., Benest, A.V., Pang, V., Bates, D., Pogson, Z.E.K., Fogarty, A., McKeever, T.M., Singapuri, A., Heaney, L., Mansur, A.H., Chaudhuri, R., Thomson, N.C., Holloway, J., Lockett, G., Howarth, P., Niven, R., Simpson, A., Tobin, M.D., Hall, I.P., Wain, L.V., Blakey, J.D., Brightling, C.E., Obeidat, M., Sin, D.D., Nickle, C., Bosse, Y., Vonk, J.M., van den Berge, M., Koppelman, G.H., Sayers, I. and Nawijn, M.C. (2021) Phenotypic and functional translation of IL33 genetics in asthma. Journal of Allergy and Clinical Immunology, 147 (1), 144-157. (doi:10.1016/j.jaci.2020.04.051).

Record type: Article

Abstract

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1, FEV 1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species–capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

Text
JACI-D-19-01391_R2 - Accepted Manuscript
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Accepted/In Press date: 14 April 2020
e-pub ahead of print date: 19 May 2020
Published date: January 2021
Keywords: IL33 SNPs, asthma phenotypes, bronchial epithelium, eQTL, functional translation

Identifiers

Local EPrints ID: 439635
URI: http://eprints.soton.ac.uk/id/eprint/439635
ISSN: 0091-6749
PURE UUID: 638066a3-cb7d-40d6-a42e-d5bb6f84c9b5
ORCID for J. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 28 Apr 2020 16:35
Last modified: 16 Oct 2021 04:01

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Contributors

Author: Maria E. Ketelaar
Author: Michael A. Portelli
Author: F. Nicole Dijk
Author: N. Shrine
Author: Alen Faiz
Author: C.J. Vermeulen
Author: C.J. Xu
Author: J. Hankinson
Author: S. Bhaker
Author: A.P. Henry
Author: C.K. Billington
Author: D.E. Shaw
Author: S.R. Johnson
Author: A.V. Benest
Author: V. Pang
Author: D. Bates
Author: Z.E.K. Pogson
Author: A. Fogarty
Author: T.M. McKeever
Author: A. Singapuri
Author: L. Heaney
Author: A.H. Mansur
Author: R. Chaudhuri
Author: N.C. Thomson
Author: J. Holloway ORCID iD
Author: G. Lockett
Author: P. Howarth
Author: R. Niven
Author: A. Simpson
Author: M.D. Tobin
Author: I.P. Hall
Author: L.V. Wain
Author: J.D. Blakey
Author: C.E. Brightling
Author: M. Obeidat
Author: D.D. Sin
Author: C. Nickle
Author: Y. Bosse
Author: J.M. Vonk
Author: M. van den Berge
Author: G.H. Koppelman
Author: I. Sayers
Author: M.C. Nawijn

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